Heterocyclic aromatic oxazole compounds and use thereof

Abstract

A heterocyclic aromatic oxazole compound of the formula (I)wherein Z is an oxygen atom; one of R and R1 is a group of the formulawherein R3 is lower alkyl, amino or lower alkylamino, and R4, R5, R6 and R7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R4, R5, R6 and R7 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R2 is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof. The heterocyclic aromatic oxazole compound and pharmaceutically acceptable salts thereof have antipyretic action, analgesic action, anti-inflammatory action, and particularly, selective inhibitory action on cyclooxygenase-2 (COX-2), and are expected to be useful as anti-inflammatory agents with less side-effects such as digestive tract disorders.

What is claimed is:  
     
       1. A compound of the formula (I):                    
       wherein 
       Z is oxygen;  
       one of R and R 1  is a group of the formula                    
       wherein 
       R 3  is a C 1-4  alkyl, amino, or C 1-4  alkylamino, and R 4 , R 5 , R 6 , and R 7  are the same or different and each is hydrogen or fluorine provided that at least one of R 4 , R 5 , R 6 , and R 7  is not hydrogen, and  
       the other of R and R 1  is (i) selected from the group consisting of phenyl, naphthyl, biphenyl, C 5-7  cycloalkyl, thienyl, furyl, and pyrrolyl, and is (ii) unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, C 1-4  alkyl, C 1-4  alkoxy, mercapto, C 1-4  alkylthio, halogen, trifluoromethyl, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, acetamido, and propionylamido; and  
       R 2  is C 1-4  alkyl;  
       or a pharmaceutically acceptable salt thereof.  
     
     
       2. A compound as claimed in  claim 1 , wherein: 
       R 1  is a group of the formula                    
       wherein 
       R 3′  is a C 1-4  alkyl or amino, and R 4′ , R 5′ , R 6′ , and R 7′  are the same or different and each is hydrogen or fluorine provided that at least one of R 4′ , R 5′ , R 6′ , and R 7′  is not hydrogen, and  
       R 2  is methyl;  
       or a pharmaceutically acceptable salt thereof.  
     
     
       3. A compound as claimed in  claim 1 , wherein: 
       R 1  is a group of the formula                    
       wherein 
       R 3″  is a methyl or amino, R 5″  is fluorine, and R 6″  is hydrogen or fluorine, and  
       R 2  is methyl;  
       or a pharmaceutically acceptable salt thereof.  
     
     
       4. A compound as claimed in  claim 3 , wherein 
       R is a C 5-7  cycloalkyl or phenyl which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, C 1-4  alkyl, C 1-4  alkoxy, mercapto, C 1-4  alkylthio, halogen, trifluoromethyl, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, acetamido, and propionplamido;  
       or a pharmaceuticall y acceptable salt thereof.  
     
     
       5. A compound as claimed in  claim 4 , wherein 
       R is cyclohexyl or 4-fluorophenyl, and  
       R 1  is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl;  
       or a pharmaceutically acceptable salt thereof.  
     
     
       6. A compound as claimed in  claim 1 , which is 
       4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,  
       5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,  
       5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,  
       4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole, or  
       5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole,  
       or a pharmaceutically acceptable salt thereof.  
     
     
       7. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       8. A method for treating an inflammatory disease, comprising administering to a subject in need thereof a pharmaceutical composition as claimed in  claim 7 .